Is CDH12 p.Pro223Ser (c.667C>T) pathogenic?

CDH12 p.Pro223Ser (c.667C>T) is classified Uncertain significance in CDH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.2082); Rare (popmax 0.21%, afr).

How common is CDH12 p.Pro223Ser (c.667C>T) in the general population?

CDH12 p.Pro223Ser (c.667C>T) is rare (popmax 0.21%, afr) (gnomAD).

What do computational predictors say about CDH12 p.Pro223Ser (c.667C>T)?

AlphaMissense predicts likely benign (score 0.2082) — an in-silico prediction, not a clinical call.

CDH12 p.Pro223Ser

c.667C>T · VCV4223649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2082 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.21%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2082	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -8.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.87, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 223 kb · p 0.95 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.21% African / African-American · 157/74,866 alleles

Filtering AF 0.183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.173%

Overall 0.0124% 199/1,610,304 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.21%	477
Admixed American	0.0387%	2,586
Remaining individualsnot grpmax-eligible	0.0176%	5,668
European (non-Finnish)	0.000679%	147,255

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDH12
Protein: p.Pro223Ser
Coding: c.667C>T
MANE Select: NM_004061
Type: single nucleotide variant
Location: chr5:21842308 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.19
Residue 223: the cadherin 2 domain

Full CDH12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH12 c.1003-3C>T Benign ★★ same type
CDH12 p.Asp780= Likely benign ★★ same type
CDH12 p.Gln60= Benign ★★ same type
CDH12 p.Glu349Asp Benign ★★ ⚠ same type
CDH12 p.Glu34Gln Benign ★★ same type
CDH12 p.Ile475Thr Benign ★★ ⚠ same type
CDH12 p.Ile598= Likely benign ★★ same type
CDH12 p.Pro213= Benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdh12-p-pro223ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown